Preventive bundles to reduce catheter-associated bloodstream infections in neonatal intensive care.

This systematic survey includes a total of 27 studies published between 2002 and 2016 on the benefit of preventive bundles for the prevention of central-line associated bloodstream infections (CLABSI) in neonatal intensive care. These studies are mainly cohort studies or studies analyzing an interrupted time series before and after intervention. The studies showed heterogeneity in terms of endpoint definitions (CLABSI), details of the implemented measures, and evidence of a publication bias favoring the use of of preventive bundles. The cumulative analysis showed a statistically and clinically significant benefit of preventive bundles to avoid CLABSI in neonatal intensive care.

Background Preterm infants and neonates in intensive care bear a high risk for nosocomial infections (NI) [1]. Level 1 and level 2 highest-care NICUs are among those risk areas where selected NI are monitored prospectively, in addition to monitoring of invasive pathogens and their antibiotic resistance profiles [2]. The findings serve to improve patient safety and quality of treatment by preventing NIs, preventing infection by multiresistent pathogens, and optimizing the use of antibiotics [3]. Local findings of the German NEO-KISS monitoring can be checked against anonymized reference data [4], [5], [6], [7], [8]. For example, there is a positive effect of prospective monitoring on the reduction of central-line associated bloodstream infections (CLABSI) [9]. The use of central (CVC) and peripheral venous catheters (PVC) has been identified as an indepentent risk factor for late-onset sepsis (LOS) in NEO-KISS participants [7]. NICUs mostly use umbilical vein catheters (UVC) and peripherally inserted central venous catheters (PICC) as central lines. Analysis and evaluation of NEO-KISS data yield important information on quantity, etiology, and pathogen range of CLABSI [10], [11]. Between January 2012 and December 2016, the median CLABSI rate (incidents per 1,000 CVC utilization days) in preterm infants was 8.62 at a birth weight (BW) of 499 g, 5.29 at BW 500 to 999 g 5. 29, and 2.35 at BW 1,000 to 1,499 g. Thus, NICUs show a significantly higher CLABSI rate than pediatric ICUs [12]. Fortunately, the CLABSI rate of preterm infants with a birth weight below 1,500 g (very low birth weight, VLBW) has decreased continuously for years now. Between 2007 and 2011, PVC-associated sepsis rates were nearly constant between 6.7 and 7.5 per 1,000 PVC utilization days [4], but most recently, between January 2012 and December 2016, the median rate per 1,000 PVC utilization days was 3.44 in ELBW preterm infants (birth weight between 500 and 999 g) and 2.18 in VLBW preterm infants (birth weight 1,000 to 1,499 g).
In 2007, the German Commission for Hospital Hygiene and Infection Prevention (KRINKO) published a recommendation for the prevention of nosocomial infections in NICU patients [13], comprising explicit recommendations for the prevention of infections associated with central lines. An update has been published recently [14] in order to support specialist NICU teams in reviewing and sustainably implementing their local standard of CLABSI prevention [15]. To merge single measures e.g. from national guidelines into an individual bundle for each hospital may lead to a significant improvement in treatment quality in the long term [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38]. The aim of this systematic investigation was to evaluate the available studies on the use of preventive bundles for the prevention of CLABSI in NICUs. This should lead to a better basic understanding of the benefits of preventive bundles in this special context and point to the characteristics of this patient population.

Methods
We searched papers in PubMed (last search Oct. 1, 2016; key words "central venous line, neonatal intensive care, prevention, preventive bundle, central line-associated bloodstream infection") and included secondary citations found in these articles and surveys to find clinical studies which were published according to peer-review procedures in Medline-listed scientific journals between 2002 and 2016. Eligible studies contained precise information on the most important aspects of infection prevention when inserting or handling central venous lines in neonatal ICU patients. Moreover, they had to present the method of diagnosing CLABSI, endpoint definitions and the effect of the preventive strategy, e.g., on the CLABSI rate in %, CLABSI incidences per 1,000 hospitalization days, or the CLABSI incidence rate per 1,000 treatment days. As randomized controlled studies have been performed very rarely in this patient population, we also included studies which used other infectiological-epidemiological methods to compare patient populations with similar basic pre-and postinterventional characteristics (implementation of preventive bundle) [39]. The most important information was entered into a structured table of findings. Where applicable, the presented survey pointed out methodological limitations of the studies, keeping in mind the basic limitations of non-prospectively randomized controlled studies. Eight studies disclosed the pre-and postinterventional CLABSI incidence rate (incidents per 100 patients), 7 studies contained evidence for an incident rate (incidents per 1,000 treatment days), and in both groups, the original publication provided information on the number of patients, number of incidents, or number of treatment days for central lines. We merged the data of this specific selection from the the total number of studies we found into an outlined meta-analysis. We used StatsDirect version 3.0.183 (Nov. 1, 2016) for meta-analysis and for calculating the combined relative risk, with a corresponding 95% confidence interval. Applying the so-called fixed effects model in combination with Cochran's Q test, the null hypothesis "there is heterogeneity between the studies" was permissible. Forest plots were used for data presentation. Additionally, the findings were analyzed by means of a funnel plot and the corresponding Egger's Test for Symmetry to show a possible publication bias.

Definition of prevention goals
Seven studies contained clear goals as to what should be accomplished for the safety of patients in a defined period of time by implementing the preventive bundle [25], [36], [47], [48], [50], [51], [53]. The aim of Cooley et al.'s initiative [47] was to reduce catheter-associated infection rates by a minimum of 50% in 12 months, which they achieved. The goal of reducing the CLABSI rate by 75% was not fully met by Fisher et al. [50], who attained 71%. Wilder et al. [48] obtained up to 92% real reduction of CLABSI rate from 2011 to 2014 versus a target rate of at least 50%, whereas Wirtschafter et al.
[25] aimed for and reached a 25% reduction of the CLABSI rate. The initial incidence rate of CLABSI at the start of the initiative is a crucial factor for formulating a clear goal. At the start, catheter-associated incidence rates in these studies [25], [36], [47], [48], [50] ranged from 1.16 up to 4.32 CLABSI/ 1,000 PICC utilization days.

Feedback of surveillance findings and compliance rates to treatment team
Periodic feedback of current CLABSI rates to the treatment team is essential to illustrate the benefits of preventive measures or the initial extent of the problem.
Many studies implemented this feedback [25], [26], [27], [29], [30], [33], [40], [44], [48], [49], [50]. McMullan et al. [40] describe a monthly feedback of CLABSI rates to the senior physician, a quarterly feedback to team members during the training progam and a 6-month formal findings report on utilization rates and CLABSI rates. According to Bizzarro et al. [26] and Dumpa et al. [30], reports on interim findings and amount of days without CLABSI were displayed in the staff break room. According to Curry et al. [27], there was positive feedback after 100 CLABSI-free days and staff members were particularly praised (pizza party). Those studies reviewing the staff-member compliance with the preventive bundles kept their staff informed about results by displaying them on notice boards [33], [44] or by distributing a newsletter [48]. Shepherd et al. [29] report that the findings of compliance checks were made accessible in the hospital's intranet.

Empowerment of staff
The assisting staff in 5 studies were entitled to stop catheter insertion when there was evidence of a failure to comply with preventive standards, which could make the insertion procedure not aseptic [24], [25], [42], [50], [51]. This medical staff followed a checklist for the decision to intervene [33], [42].

Pre-assembled flushing syringes
As part of the preventive bundle, pre-assembled flushing syringes with sterile physiological saline solution were used in 3 multicenter studies [24], [25], [51] in order to eliminate the risk of contamination when filling the syringe manually.

Discussion
By analyzing and meta-analyzing 27 studies, this survey proves the benefit of preventive bundles on the prevention of CLABSI in premature NICU patients. This should motivate NICU teams to define local preventive bundles according to the latest KRINKO recommendations and to implement these measures sustainably [55]. In this context, the NEO KISS module provides a well-established and standardized instrument for the prospective surveillance of CLABSI in premature infants, which allows NICU teams to present and provide feedback on the long-term effects of preventive bundles to the entire team. The problem of safe and effective skin antisepsis in very immature preterm infants of BW<1,500 g is still unresolved [56], especially in the first two weeks of life when the skin is extremely vulnerable. Many studies use different concentrations of chlorhexidine gluconate (CHG) for skin antisepsis in premature infants, despite the fact that CHG may cause serious local skin irritations [57] and is 14/20 resorbed systemically [56], [58], [59], [60]. To date, it remains unclear which long-term consequences are caused by CHG exposure in premature infants. Based on an Orphan Drug approval of the European Medicines Agency (EMA), the KRINKO recommendations still name Octenidin 0.1% as the first-choice skin antiseptic. However, there is no commercially available ready-to-use product without 2% phenoxyethanol or 70% isopropanol. Even with Octenidin 0.1%, there is evidence of skin lesions in very immature preterm infants during the first 2 weeks of life [61]. Hence, the KRINKO currently recom-mends limiting exposed skin areas by using sterile drapings before skin antisepsis. Preventive bundles to reduce CLABSI in NICUs are part of an NI prevention master plan for premature infants [13]; see also Bowen's initiative for quality improvement [49]. Besides a preventive bundle for PICCs and PVCs, the author's list of recommended preventive measures comprises additional information on structural-organisational aspects (e.g., patient-related medical products/stethoscopes, processing medical traps, administering mother's milk and probiotics, kangarooing, visitor regulations and antibiotic stewardship in NICUs). In Germany, there are additional measures in place such as weekly colonization screening to detect and stop the nosocomial transfer of antibiotic-resistant pathogens at an early stage [62], precautions for the aseptic reconstitution or preparation of medical products for parenteral use [63], [64], and concepts to decolonize premature infants colonized or infected with methicillin-resistant S. aureus [65].

Limitations
The investigated studies differed regarding the implementation of preventive bundles and definition of endpoints (see Table 2). The effect of different definitions can be made clear when we look at the consequences of the new 2008 definition of CLABSI caused by potential contaminants of blood culture, i.e., skin flora bacteria. According to the new CDC definition [54], coagulase-negative staphylococci (CoNS) must be detected in any case by means of two or more independently drawn blood cultures. Blood culture results reveal CoNS as the most frequent source of infection in premature NICU patients with late-onset sepsis diagnosed after the third day of life. Schulman et al. [52] describe a decrease of CoNS-caused CLABSI from 59% to 41% based only on the retrospective adaptation of CDC definitions after 2008. Accordingly, CoNS were not detected in two separately drawn blood cultures in 17% of CLABSI before 2008. Premature infants have a very low blood volume (100 ml/kg equalling 50 ml in an infant with a body weight of 500 g). Aerobic blood culture bottles are approved for this small blood volume, but fillings frequently fall short of the recommended minimum volume of 1 ml [66], [67], let alone drawing two such blood cultures of 1 ml each before starting an empirical antibiotic therapy. For the same reasons, it is not possible in neonatal intensive care to do routine parallel central and peripheral venous blood cultures in order to define the differential time to positivity. Relevant NEO KISS definitions, i.e., before the update in 2016, state "A single proof of coagulase-negative staphylococci does not necessarily rule out the diagnosis of clinical sepsis. Clinical sepsis may be diagnosed even with one proof of CoNS in blood culture when classified as contamination while not meeting CoNS sepsis criteria but meeting criteria for clinical sepsis". A "microbiologically confirmed sepsis with CoNS as only pathogen" must be confirmed through at least one additional laboratory parameter and a minimum of two additional clinical criteria. To this extent the single proof of CoNS in the blood culture of a preterm patient with clinical sepsis may be assessed as contamination ("clinical sepsis") or detection of a pathogen ("microbiologically verified sepsis with CNS as only pathogen"). Moreover, CLABSIs are not established as certain catheter-originating infections [66]. Sepsis was considered to be a CLABSI when the patient had a central vascular access within 48 hrs before infec-tion or at the beginning of the infection, and when there was no other primary focus of infection defined by imaging or clinical evaluation. Semi-quantitative roll-plate culture of catheter tips [68] is not part of surveillance definitions for preterm infants, although significant growth (e.g., ≥15 CFU according to Maki's method) points to the catheter as the probable source of the infection. CLABSI surveillance criteria are not decisive factors for clinical assessment of suspected late-onset infections. The benefit of a preventive bundle can only be assessed realistically when we know how many times the components are definitely accomplished. Most study protocols of this survey (20 of 27; 74%) included a verification of compliance, but methods of near-patient monitoring and feedback differed widely. Supervision of compliance with hand hygiene seems highly useful [69]. This also applies to other crucial checkpoints, such as skin antisepsis and maximum barrier measures for PICC placement, disinfection of hubs, needle-free connective valves and other injection points before each manipulation, or procedural details for dressing and IV system changes. Many multicenter studies obliged participating centers to supervise and secure compliance with preventive measures. Well-trained hygiene specialist staff are highly suitable for checking the compliance through aimed auditing of NICUs, but such staff with sufficient working time are not available everywhere. Checklists and especially a strict provision requiring two licensed nurses for all critical manipulations like dressing changes or line changes are useful. In some studies, there were specialist teams to perform placement and maintenance of central lines [25], [27], [28], [29], [35], [36], [38], [43], [47], [48], whereas most German NICUs aim at personal responsibility in letting nurses and doctors perform necessary actions autonomously. Considerable efforts are necessary for the new introduction of preventive bundles concerning knowledge transfer courses and training skills, which must be taken into account, e.g., in terms of working time when planning the practical implementation of such measures [55]. The scientific examination of preventive bundles is not suited to showing the specific benefit of individual bundle components. Nevertheless, merging individual measures of proven benefit in term of reducing infection risks may result in a higher overall effect on CLABSI rates. In conclusion, our evaluation impressively confirms the benefit of preventive bundles regarding the prevention of CVC-associated infections in premature NICU patients. The heads of German NICUs should examine local preventive strategies according to KRINKO recommendations. Preventive bundles should be defined together with all involved professional groups and sustainably implemented in daily clinical routine. 16

Notes Competing interests
The authors declare that there are no conflicts of interest. Prof. Simon is coordinator of the working group on neonatal intensive care of the German Commission for Hospital Hygiene and Infection Prevention affiliated to the Robert Koch Institute in Berlin, Germany. Prof. Geffers is leader of the NEO-KISS surveillance module of the German National Reference Center for Surveillance of Nosocomial Infections, Institute for Hygiene and Environmental Medicine at the Charité in Berlin, Germany.